The central respiratory network controls breathing and produces three distinct patterns of activity: eupnea, gasping, and sighs. This proposal will focus on sigh generation. Periodic sigh generation is required to maintain normal blood gas levels, and the inability to generate sighs is related to serious respiratory conditions such as lung atelectasis. Sighs also play an important role in triggering arousal, and the loss of sighs has been related to an increased risk of SIDS. The role of sighs in maintaining blood gas levels and triggering arousal during hypoxia suggests that sighs may be produced when metabolic activity is altered with the purpose of coordinating and resetting the sparsely connected central respiratory networks. Unfortunately, the mechanisms underlying sigh generation and periodicity remain unclear. Previous studies have focused on the role of voltage-gated calcium channels and glutamatergic synapses that might be involved in sigh generation. In the current proposal we offer a different approach to uncovering and understanding these mechanisms. Specifically, we propose to examine neuron-glia interactions for novel signaling pathways that underlie sigh generation and periodicity. These interactions will be tested in vivo and also in vitro using a transverse brainstem slice preparation containing the preB? tzinger Complex (preB? tC). The preB? tC is the presumed inspiratory central rhythm generator. In vitro it can produce the rhythmic patterns underlying eupneic activity, gasping, and sighs. In addition, it produces a stereotypical response to hypoxia that closely mimics the in vivo hypoxic ventilatory response. The proposal is divided into three parts. The first part is aimed to test the role of glia on sigh generation and also to investigate how chemical and light stimulated inhibition/excitation of glia affect the response to different neuromodulators and environmental challenge such as hypoxia. The second part is aimed to reveal the cellular mechanism supporting sigh generation. We search for a source of self-sustained oscillations leading to a global synchronization. The last past of the proposal is focused on theoretical modeling of the neuron-glia interaction network. By creating a new model of the respiratory network, which incorporates the collected data, we will be able to mimic different neuromodulatory and metabolic states of the system and thus use this model to investigate new testable hypothesis.